Until recently, anthrax was primarily a concern of individuals working in animal husbandry and military planners concerned about the potential use of anthrax spores as an agent of biological warfare. The use of anthrax as an agent of bioterrorism on civilian populations was a theoretical risk, heightened by the discovery that certain rogue nations (notably Iraq, Syria, and China) either had developed or were attempting to develop anthrax or other biologic agents as a weapon of mass destruction, The post- September 11 release of anthrax spores resulted in five civilian deaths, eighteen infections, and required that more than 30,000 individuals to undergo prophylactic antibiotic therapy. This event also highlighted the need for improved vaccines that would be appropriate for pre- or post- exposure immunization of civilian and military populations against potential bioterrorism agents, including anthrax and plague, Vaccines combining protective antigens from different microorganisms with potential for use against civilian or military populations as biological warfare/biological terrorism agents would be advantageous because they would both broaden the coverage of such vaccines and reduce the overall number of immunizations. The first logical combination to examine would be rPA from B. anthracis and F1-V from Y. pestis since they have individually been shown to induce protective responses. Combining vaccines to decrease the number of immunizations and to increase vaccine coverage is not a new concept in vaccine development and combination vaccines such as DTP and MMR have been used for many years. However, several examples of immunologic interference between individual components of combination vaccines have been observed both in clinical trials and in laboratory tests. We are therefore proposing to examine the potential of a combined vaccine consisting of rPA and F1-V with the specific objective of determining synergy or interference between the vaccine components. For this application, we propose to address a number of interrelated questions regarding immunization with a combined vaccine containing rPA and F1-V as immunogens to protect against anthrax and plague.